Severe human periodontal disease affects 30-40 percent of all Americans by age 60. The annual direct financial cost of this disease probably exceeds one billion dollars. Although many details relating to its etiology have become known in the past decade, knowledge of the underlying mechanisms for the bone resorption, which is the hallmark of the disease, remains incomplete. A role for lymphocytes in the pathogenesis has long been suspected, and recent studies have shown that B lymphocytes may be of particular importance. B cells and plasma cells are the primary inflammatory cells in the severe lesion, and peripheral blood lymphocytes from patients with severe periodontitis are hyperresponsive to polyclonal B-cell mitogens in vitro. Because the bacteria in dental plaque produce and release large amounts of B-cell mitogens (e.g., LPS), and because mitogen-activated B cells produce osteolytic factors, it is possible that B cell hyperresponsiveness to mitogens plays a central role in severe periodontitis. In order to better understand genetic regulation of B lymphocyte responses to mitogens, I have studied a mouse model (strain SM/J) in which genetically determined hyperresponsiveness to B-cell mitogens occurs. In the proposed studies, I describe experiments which would allow determination of the number of genes involved in the SM/J strain hyperresponse to B-cell mitogens, the linkage of these genes to known genetic markers, and how these genes interact with other lymphocyte regulatory genes. I also will study cell-surface markers of B cells that may relate to hyperresponsiveness, and will determine whether the cell cycle kinetics and transcriptional activities of SM/J strain hyperresponsive B cells differ from those of normal-responder mice. Finally, I will study possible regulatory defects in the B-cell responses of the SM/J strain using tolerance to sheep red blood cells as a model system. I believe the proposed experiments will be of value in determining the underlying pathogenic mechanism of periodontal disease, and other diseases in which the B cell plays a major role.